This research proposal seeks information about the nature of human antibodies that inactivate factor VIII procoagulant (antihemophilic factor) activity and the antigenic determinants with which they react. It is based on the contention that effective means for treatment and/or prevention of inhibitors to factor VIII are not likely to be developed until this basic information is available. There are five specific goals: 1. Immunochemical characterization of the structure and function of factor VIII procoagulant protein (VIII:C) using high-titer human anti-VIII:C and hybridoma anti-VIII:C as probes. 2. Preparation of monoclonal antibodies to the factor VIII procoagulant protein by both murine-murine fusions and human-murine fusions. 3. Preparation of anti-idiotype antibodies that react with specific determinants of human anti-VIII:C antibodies. These antibodies will be obtained by both conventional (rabbit immunization followed by antiserum adsorption) and hybridoma methods. The anti-idiotype antibodies will be used with a panel of high titer human anti-VIII:C to determine if there are common determinants shared by different human anti-VIII:C. 4. Immunochemical analysis of human anti-VIII:C to determine heavy and light chain classes by methods that are independent of coagulation assays. 5. Identification of the organ and cell type responsible for VIII:C synthesis.